Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
Very long chain acyl CoA dehydrogenase (VLCAD) is one of the four acyl-CoA dehydrogenases. VLCAD is a homodemeric mitochondrial protein that catalyzes the first step in the β-oxidation of fatty acids. VLCAD has activity mainly toward CoA-esters of fatty acids with 16-24 carbons in length and is responsible for more that 80% of palmitoyl-CoA dehydrogenation in human tissues and mammalian organs and cells, indicating that it is the major contributor in mitochondrial fatty acid oxidation.
VLCAD deficiency is an autosomal recessive genetic disorder first identified in 1993 and now considered as the second most common mitochondrial β-oxidation disorder. The associated disease presents with three main phenotypes. The most severe form of VLCAD deficiency presents with neonatal cardiomyopathy and hepatic failure and is generally fatal in the first year of life. An infantile phenotype typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly without cardiomyopathy. The mildest phenotype is associated with later onset episodic myopathic form with intermittent rhabdomyolysis, muscle cramps and/or pain and exercise intolerance. To date, more than 100 pathologic mutations are known including null (typically associated with the most severe form of the disease) as well missense mutations that occur throughout the VLCAD protein and are associated with the milder forms of the disease. Missense mutations result in reduced enzymatic activity and/or reduced stability of the protein leading to lower steady state levels of acyl-CoA activity in mitochondria. Upon diagnosis of VLCAD disease the effort is placed on the prevention of its manifestations. Individuals are typically placed on a low-fat formula with supplemental calories provided through medium-chain triglycerides. Superior methods of treatment and prevention are needed.